New solvates of an old drug compound (phenobarbital): structure and stability.
New solvates of an old drug compound (phenobarbital): structure and stability.
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DOI：
10.1021/jp409201v
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发表时间：
2014-03
期刊：
影响因子：
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通讯作者：
N. Zencirci;U. Griesser;T. Gelbrich;V. Kahlenberg;R. K. Jetti;D. Apperley;R. Harris
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文献类型：
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作者：
N. Zencirci;U. Griesser;T. Gelbrich;V. Kahlenberg;R. K. Jetti;D. Apperley;R. Harris
本文详细研究了苯巴比妥这种重要的药物化合物的溶剂形成过程。制备了含有乙腈、硝基甲烷、二氯甲烷和1,4-二恶烷的单溶剂化物，并通过单晶和粉末x射线衍射、热分析方法、傅里叶变换红外光谱、拉曼光谱和固态核磁共振光谱对其进行了表征。这些化合物的热溶解主要产生多晶型III、II和i的混合物。在低相对湿度（25°C）下，溶剂化物转化为多晶型III，在高相对湿度下，一水化合物和亚稳多晶型IV和VI可以作为额外的溶解产物存在。这些结果突出了脱溶反应的潜在复杂性，并说明严格控制环境条件是生产相纯药物化合物原料的先决条件。在水介质中的转化产生一水合物。在室温下，1,4-二氧六环单溶剂化物由于其50%的溶剂分子的有序/无序，经历了可逆的单晶到单晶的相变。双极脱相核磁共振实验表明溶剂分子具有相对的可移动性。氘核磁共振光谱证实了二氧六烷溶剂分子的这一结论。一种难以捉摸的1,4-二恶烷半酸盐的晶体结构也被确定。本研究清楚地表明苯巴比妥存在“瞬态溶剂化物”。为了更好地理解不同溶剂如何影响特定晶型的结晶，必须考虑这种不稳定相的形成。
The solvent formation of phenobarbital, an important drug compound with an unusually complex polymorphic behavior, was studied in detail. Monosolvates with acetonitrile, nitromethane, dichloromethane, and 1,4-dioxane were produced and characterized by single-crystal and powder X-ray diffraction, thermoanalytical methods, FT-IR, Raman, and solid-state NMR spectroscopy. Thermal desolvation of these compounds yields mainly mixtures of polymorphs III, II, and I. At a low relative humidity (25 °C) the solvates transform to polymorph III, and at higher relative humidity the monohydrate and the metastable polymorphs IV and VI can be present as additional desolvation products. These results highlight the potential complexity of desolvation reactions and illustrate that a tight control of ambient conditions is a prerequisite for the production of phase-pure raw materials of drug compounds. Transformation in aqueous media results in the monohydrate. Below room temperature, the 1,4-dioxane monosolvate undergoes a reversible single-crystal-to-single-crystal phase transition due to the ordering/disordering of 50% of its solvent molecules. Dipolar-dephasing NMR experiments show that the solvent molecules are relatively mobile. Deuterium NMR spectra reinforce that conclusion for the dioxane solvent molecules. The crystal structure of an elusive 1,4-dioxane hemisolvate was also determined. This study clearly indicates the existence of "transient solvates" of phenobarbital. The formation of unstable phases of this kind must be considered in order to better understand how different solvents affect the crystallization of specific polymorphs.